tbuckley/cabot-search huggingface dataset:
Abstract 4245: QL301, a PD-L1 dependent 4-1BB agonist with enhanced preclinical anti-tumor efficacy and minimal liver toxicity
Authors: Shenda Gu, Irene Tang, Shirley Mihardja, Wei Wei Prior, Hieu V. Tran, Allan Chan, Anna McClain, Aaron Kurtzman, Shihao Chen, Youguang Luo, Xiaoyan Kang, Xiaoran Wu, Qingmei Zheng, Guodong Jia
Journal: Cancer Research (2022)

Abstract 4-1BB (CD137, TNFRSF9) is a potent co-stimulatory receptor found on T and NK cells. Activation of 4-1BB requires receptor clustering, which is naturally mediated by the endogenous trimeric 4-1BB ligand. Cross-linking via agnostic monoclonal antibodies can also activate 4-1BB but has generally resulted in unwanted side effects, mainly liver toxicity. To address the shortcomings of 4-1BB agonists, we have developed QL301, a PD-L1 x 4-1BB bispecific antibody that conditionally activates 4-1BB only when concurrently engaged to PD-L1, an immune checkpoint mediator elevated in the immuno-suppressive tumor microenvironment. The IgG1 backbone of QL301 was mutated to eliminate Fc gamma receptor-dependent functions such as antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), thereby preventing depletion of effector immune cells and non-specific activation of 4-1BB through Fc gamma receptor binding. In addition, QL301 blocks the suppressive interaction of PD-1 with PD-L1. Therefore, through a combination of 4-1BB agonism and PD-L1 blockade, QL301 provides both a co-stimulatory signal and the release of a suppressive signal to reinvigorate anti-tumor immune response. In vitro, QL301 induced robust cytokine release and expansion of CD8+ T cells conditional on the presence of tumor or antigen presenting cells expressing PD-L1. In xenograft and transgenic mice models, QL301 had potent anti-tumor effect that was superior to PD-L1 monoclonal antibodies. Tumor regression correlated with the expansion of CD8+ T cells. In addition, QL301 potentiated tumor cell killing mediated by an EGFR targeted CD3 bispecific antibody, providing a basis for combination therapy. In non-human primates, QL301 was well tolerated up to 30 mg/kg. There was no chronic elevation of serum AST and ALT levels, and histopathology analysis showed minimal inflammation of liver tissue. A phase 1 clinical trial to evaluate the safety, tolerability, and early efficacy of QL301 is currently ongoing. Citation Format: Shenda Gu, Irene Tang, Shirley Mihardja, Wei Wei Prior, Hieu V. Tran, Allan Chan, Anna McClain, Aaron Kurtzman, Shihao Chen, Youguang Luo, Xiaoyan Kang, Xiaoran Wu, Qingmei Zheng, Guodong Jia. QL301, a PD-L1 dependent 4-1BB agonist with enhanced preclinical anti-tumor efficacy and minimal liver toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4245.
Abstract 5404: Identification prognostic markers for patients with defective mismatch repair in colorectal cancer: <i>MKI67, TPR</i>,<i>TCHH</i>
Authors: Zheng Liu, Jingfang Lv, Hongmei Zhao, Xishan Wang, Dongliang Wang
Journal: Cancer Research (2022)

Abstract Background: Deficiency in the mismatch repair system (dMMR/MSI-H) is found in approximately 15-20% of colorectal cancer. However, the prognostic evaluation of patients with dMMR CRC in stage II/III is still incomplete and lacks systematic studies. Methods: In this study, we systematically analyzed the prognostic risk of 32 patients with dMMR CRC in stage II/III based on whole-exome sequencing and clinical characters. Differentially mutated genes (DMGs) were explored by fisher-test. For survival analysis, Kaplan-Meier survival curves were generated and compared using the log-rank test. Univariate and multivariate Cox regression analyses were performed to evaluate association DMGs with progression-free survival (PFS). Furthermore, these genes were verified in TCGA Pan Can Atlas 2018 cohort. Results: The patients with dMMR CRC in stage II/III have the highest levels of MKI67, TCHH and TPR mutations (53.4%). Across all 73 patients with MSI-H, the mutational frequencies of MKI67, TCHH and TPR were (30%, 24% and 15%, respectively), which were associated with PFS (P=0.029, P=0.00261 and P=0.00298, respectively). That means the patients with MKI67, TCHH and TPR mutations have poor prognosis. Furthermore, MKI67, TCHH and TPR mutations were verified as independent factors for dMMR/MSI-H colorectal cancer both in training cohort and validation cohort. Conclusions: MKI67, TCHH and TPR were potential prognostic markers for dMMR colorectal cancer. Based on these data and rationale, we suggest that mutations in all exons of these 3 genes should be integrated into predictive biomarker panels for patients with dMMR/MSI-H, aiming to provide more accurate guidance for the selection of personalized diagnosis. Keywords: MKI67, TPR, TCHH, Defective Mismatch Repair, Colorectal Cancer, Prognostic Markers Citation Format: Zheng Liu, Jingfang Lv, Hongmei Zhao, Xishan Wang, Dongliang Wang. Identification prognostic markers for patients with defective mismatch repair in colorectal cancer: MKI67, TPR,TCHH [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5404.
Abstract 5550: QLS31904: An anti-DLL3/CD3 bispecific antibody for T cell immunotherapy of small cell lung cancer
Authors: Liuqing Yang, Ruimei Li, Jiahua Jiang, Hongliang Qian, Hongxiu Ge, Ting Lu, Yan Fang, Jun Liu, Shuyong Zhao
Journal: Cancer Research (2022)

Abstract Background: More than 150,000 patients are diagnosed with small cell lung cancer (SCLC) each year in the world. Standard of care for patients at different stages of SCLC includes radiation, etoposide, cisplatin/carboplatin, and atezolizumab. However, relapse is quite common. Therefore, there is a strong need to develop a more effective treatment. Delta-like ligand 3 (DLL3) is a target selectively expressed in SCLC rather than normal tissue. We have developed an anti-DLL3/CD3 bispecific antibody QLS31904 that is engineered to direct and activate T cells through CD3 to kill SCLC cells expressing DLL3. Methods: Tumor cell killing, T cell activation, and cytokine production of QLS31904 in a concentration range were assessed in the presence of SCLC cells and human T cells in vitro. Antitumor activity of QLS31904 was evaluated in SCLC xenograft models, in which NCG mice were co-implanted with SHP-77 and human T cells first, then treated with intraperitoneal QLS31904 or control IgG1AA isotype. The in vivo tumor growth inhibition was assessed. Pharmacokinetic analyses were performed in non-human primates (NHP). The cross-reactivity of QLS31904 with NHP DLL3 and CD3 were established, and the tolerability was also evaluated in NHP model. Results: QLS31904 displayed the anticipated bispecific binding properties and mediated potent and selective lysis of DLL3-positive cancer cell lines through recruitment and activation of human T cells. No cytokine activation was observed with human peripheral blood mononuclear cell alone. In xenograft models, QLS31904 induced significant tumor growth inhibition at doses as low as 20 µg/kg, including complete regression of established tumors. QLS31904 exhibits about 100 hours of T1/2 in NHP, supporting feasibility of weekly dosing. QLS31904 was well tolerated with no related adverse findings up to the highest tested dose (five weekly doses of 10mg/kg) in NHP. Conclusions: QLS31904 has an impressive efficacy and safety profile in the preclinical studies, making it a potentially viable option for DLL3-expressing SCLC in the clinical setting. Citation Format: Liuqing Yang, Ruimei Li, Jiahua Jiang, Hongliang Qian, Hongxiu Ge, Ting Lu, Yan Fang, Jun Liu, Shuyong Zhao. QLS31904: An anti-DLL3/CD3 bispecific antibody for T cell immunotherapy of small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5550.
Abstract LB507: Towards elucidating the role of RNA modifications in cancer by improving the quantitative accuracy of mass spectrometric profiling of RNA modifications
Authors: Norman H. Chiu, Jennifer H. Simpson, Renata L. Fleming, Jian Teng, Bakhos A. Tannous
Journal: Cancer Research (2022)

Abstract The molecular structure of both coding and non-coding RNA is frequently altered by the enzymatic activity of either writer or eraser of RNA modifications. Since the RNA functions are dependent on its molecular structure, cellular activities that involve specific RNA molecule(s) can potentially be regulated by the reversible nature of RNA modifications. There are more than 140 known RNA modifications. Mass spectrometry is a proven technique for the identification of RNA modifications. However, due to the lack of ribonucleoside standards and biases in normalizing the level of RNA modifications, it remains a challenge to perform the quantitative analysis of multiple RNA modifications that may co-exist in a biological sample. Our group has recently developed a method for standard-free quantitative epitranscriptomic profiling (SqEP) that allows us using mass spectrometry to accurately determine the abundancy of each detectable RNA modification without using any ribonucleoside standards to calibrate the detection signals. Thus, the SqEP method can be used for the untargeted analysis of RNA modifications. It also allows us to directly compare the level of different RNA modifications that are detectable in an individual cell line. This is an important feature for studying the relationships between various RNA modifications. Using glioblastoma (GBM) as our model, the results from using the SqEP method to determine the level of specific RNA modifications in patient-derived GBM cell lines were shown to be more accurate than the existing methods, and complied with the gene expression data from GBM patients that are available in the Cancer Genome Atlas (TCGA) program. Citation Format: Norman H. Chiu, Jennifer H. Simpson, Renata L. Fleming, Jian Teng, Bakhos A. Tannous. Towards elucidating the role of RNA modifications in cancer by improving the quantitative accuracy of mass spectrometric profiling of RNA modifications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB507.
Abstract 1490: Development of a 5-FU modified miR-129 mimic as a novel therapeutic for non-small cell lung cancer
Authors: Ga-Ram Hwang, John G. Yuen, Hannah Farley, Jingfang Ju
Journal: Cancer Research (2022)

Abstract Lung cancer is the leading cancer type of cancer-related deaths in the U.S., with non-small cell lung cancer (NSCLC) accounting for a majority of cases. Despite innovations in cancer therapeutics, due to resistance to these therapeutics, the 5-year survival rate for patients with metastatic lung cancer has remained poor. As a result, there is an urgent need to develop new and effective therapeutics, including the study of RNA-based therapeutics. Previous studies from our laboratory have shown that 5-fluorouracil (5-FU) modified tumor suppressor miRNAs significantly enhance the therapeutic efficacy, stability, and deliverability of miRNAs in colorectal cancer (CRC) and pancreatic cancer. In this study, we have characterized the therapeutic potential of miR-129 modified with 5-FU (5-FU-miR-129) in non-small cell lung cancer in vitro via Annexin V staining, cell cycle analysis, and Western Blot. 5-FU-miR-129’s therapeutic potential was also assessed in vivo via IVIS imaging of NSCLC xenografts. We have demonstrated that 5-FU-miR-129 can induce apoptosis (7.2-fold in A549 and 2.9-fold in Calu-1) and cell cycle arrest (12.7-fold change in G1/S phase ratio in A549) in NSCLC in vitro. Furthermore, 5-FU-miR-129 has been found to retain target specificity by downregulating miR-129 targets BCL2 and HMGB1 in a cell line-dependent manner. As was observed in previous studies, we have also demonstrated the ability of 5-FU-miR-129 to be delivered in cancer cells without the use of a transfection vehicle in vitro. Finally, we were also able to demonstrate the therapeutic potential of 5-FU-miR-129 in inhibiting NSCLC tumor growth in vivo, as seen by a significantly decreased change in tumor growth by 37 days post-treatment in the 5-FU-miR-129 treated group compared to the negative control group (79.8% reduction in tumor growth). In addition, we observed a significant increase in survival probability and a reduced hazard ratio in mice treated5-FU-miR-129 when compared to the negative control group. Furthermore, we did not observe any visible side effects (hair loss) of mice treated with 5-FU-miR-129 compared to chemotherapeutic drugs 5-FU and gemcitabine (Gem). 5-FU-miR-129’s therapeutic potential in NSCLC further demonstrates the potential for modified miRNAs as a platform technology in cancer therapeutics. Citation Format: Ga-Ram Hwang, John G. Yuen, Hannah Farley, Jingfang Ju. Development of a 5-FU modified miR-129 mimic as a novel therapeutic for non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1490.
Abstract LB049: Spatial immune determinants of ICB response in STK11-mutated non-small cell lung cancer
Authors: Florian Uhlitz, Douglas Linn, Elsa Beyer Krall, Jacklynn Egger, Hira Rizvi, Jason Chang, Benjamin Nicholson, Rami Vanguri, Andrew Chow, Matthew Hellmann, Sohrab Shah
Journal: Cancer Research (2022)

Abstract Response to immune checkpoint blockade (ICB) in non-small cell lung cancers (NSCLC) is associated with recurring mutations in tumor suppressor genes STK11 and TP53. Whereas STK11-mutated patients are mostly insensitive, TP53-mutated patients commonly respond to ICB. Previous studies have linked mutational status in these genes to differences in cell type composition of the tumor microenvironment (TME). However, it remains unclear if differences in cell type compositions as well as cell-cell interactions in turn could account for the observed differences in treatment response and overall survival in NSCLC. Here, we perform spatial profiling of immune and stromal phenotypes in the TME of 119 NSCLC patients using imaging mass cytometry (IMC) on tissue microarrays (TMA). Matching data from MSK IMPACT (clinical sequencing) was used to establish mutation profiles and therapeutic response was included in the analysis. We find that STK11-mutated NSCLC is characterized by decreased CD4 T cell and increased neutrophil abundance, while TP53-mutated NSCLC is associated with increased CD8 T cell and decreased endothelial cell abundance. Accordingly, we stratified the patient population into TME classes by cell type composition. We found that while mutational status does not inform overall survival in our cohort, stratification by cell type abundance strongly associates with patient outcome (p-value: 0.000146, logRank test). Patients with neutrophil-rich TMEs show worse overall survival (25% 5-year survival), while patients with increased endothelial cell and macrophage abundance have a tendency to live longer (80% and 75% 5-year survival respectively). Furthermore, we interrogate pairwise proximity of immune cell types and states to construct cellular networks in NSCLC. Together, our findings suggest that TME cell type composition and cellular networks are potential molecular determinants for ICB therapeutic response in NSCLC patients. Citation Format: Florian Uhlitz, Douglas Linn, Elsa Beyer Krall, Jacklynn Egger, Hira Rizvi, Jason Chang, Benjamin Nicholson, Rami Vanguri, Andrew Chow, Matthew Hellmann, Sohrab Shah. Spatial immune determinants of ICB response in STK11-mutated non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB049.
Rapid evaluation of COVID-19 vaccine effectiveness against symptomatic infection with SARS-CoV-2 variants by analysis of genetic distance
Authors: Lirong Cao, Jingzhi Lou, See Yeung Chan, Hong Zheng, Caiqi Liu, Shi Zhao, Qi Li, Chris Ka Pun Mok, Renee Wan Yi Chan, Marc Ka Chun Chong, William Ka Kei Wu, Zigui Chen, Eliza Lai Yi Wong, Paul Kay Sheung Chan, Benny Chung Ying Zee, Eng Kiong Yeoh, Maggie Haitian Wang
Journal: Nature Medicine (2022)

Timely evaluation of the protective effects of Coronavirus Disease 2019 (COVID-19) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern is urgently needed to inform pandemic control planning. Based on 78 vaccine efficacy or effectiveness (VE) data from 49 studies and 1,984,241 SARS-CoV-2 sequences collected from 31 regions, we analyzed the relationship between genetic distance (GD) of circulating viruses against the vaccine strain and VE against symptomatic infection. We found that the GD of the receptor-binding domain of the SARS-CoV-2 spike protein is highly predictive of vaccine protection and accounted for 86.3% (P = 0.038) of the VE change in a vaccine platform-based mixed-effects model and 87.9% (P = 0.006) in a manufacturer-based model. We applied the VE-GD model to predict protection mediated by existing vaccines against new genetic variants and validated the results by published real-world and clinical trial data, finding high concordance of predicted VE with observed VE. We estimated the VE against the Delta variant to be 82.8% (95% prediction interval: 68.7-96.0) using the mRNA vaccine platform, closely matching the reported VE of 83.0% from an observational study. Among the four sublineages of Omicron, the predicted VE varied between 11.9% and 33.3%, with the highest VE predicted against BA.1 and the lowest against BA.2, using the mRNA vaccine platform. The VE-GD framework enables predictions of vaccine protection in real time and offers a rapid evaluation method against novel variants that may inform vaccine deployment and public health responses.
Abstract 399: The glucocorticoid receptor and β-catenin interact in prostate cancer cells and their co-inhibition attenuates stemness and docetaxel resistance
Authors: Shannalee R. Martinez, Catherine C. Elix, Pedro T. Ochoa, Evelyn S. Sanchez-Hernandez, Hossam R. Alkashgari, Greisha L. Ortiz-Hernandez, Lubo Zhang, Carlos A. Casiano
Journal: Cancer Research (2022)

Abstract The efficacy of anti-androgen receptor (AR) therapies and taxane-based chemotherapy for the treatment of advanced prostate cancer (PCa) is hindered by the development of therapy resistance. Our previous studies demonstrated that docetaxel (DTX)-resistant PCa cells activates a transcriptomic program associated with stemness and display cancer stem cell (CSC) properties, consistent with the notion that CSCs within prostate tumors contribute to chemoresistance. Glucocorticoid receptor (GR) signaling is a critical mediator of resistance to AR-targeted therapy, and has been recently implicated in the development of PCa cell tumorsphere formation and chemoresistance. Like GR, β-catenin is overexpressed in metastatic and therapy-resistant tumors, and is considered a key regulator of cancer stemness and androgen-targeted therapy resistance. Given the structural and functional overlap between GR and AR, a known interacting partner of β-catenin, we hypothesized that GR also interacts with β-catenin to support stemness and chemoresistance in PCa cells. We observed that treatment with the glucocorticoid dexamethasone induces enhanced nuclear accumulation of both GR and β-catenin in DTX-resistant PCa cells compared to their DTX-sensitive counterparts. Knockdown studies revealed that GR and β-catenin do no regulate each other at the protein level. However, using whole cell and nuclear co-immunoprecipitation, we demonstrated the interaction between GR and β-catenin in both DTX-resistant and DTX-sensitive PC3, DU145, and 22RV1 cells. Pharmacological inhibition and RNA interference-mediated silencing of GR with concomitant inhibition of β-catenin enhanced DTX cytotoxicity in resistant PCa cells grown in both adherent and spheroid cultures, and decreased CD44+/CD24- cell populations in tumorspheres. These results indicate that both GR and β-catenin interact and influence stemness, and may be promising therapeutic targets to overcome PCa chemoresistance. Citation Format: Shannalee R. Martinez, Catherine C. Elix, Pedro T. Ochoa, Evelyn S. Sanchez-Hernandez, Hossam R. Alkashgari, Greisha L. Ortiz-Hernandez, Lubo Zhang, Carlos A. Casiano. The glucocorticoid receptor and β-catenin interact in prostate cancer cells and their co-inhibition attenuates stemness and docetaxel resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 399.
Abstract 533: A study of sequencing circulating cell free DNA from lung cancer patients
Authors: Zhigang Kang, Liang Cao
Journal: Cancer Research (2022)

Abstract Precision oncology requires accurate cancer molecular information. While widely used to characterize tumors, tissue biopsy is limited in patient follow-up due to its invasive nature and the lack representation of the entire tumor bulk. To develop the method of circulating cell free DNA (cfDNA) for obtaining clinically valuable sequence information, we isolated cfDNA from the plasma samples of 10 advanced metastatic lung cancer patients and performed next generation sequencing (NGS) using a unique molecular marker (UMI) integrated 275-gene-target-panel at the average depth of 4,000 X coverage. We were able to identify common mutants of lung cancer driver genes, e.g. EGFR, KRAS, DNMT3 and TP53 with high confidence. In one example, the TKI resistant EGFR mutant T790M was found coexisting with EGFR 746-750del and TP53 splice variant in a baseline sample of a patient progressed from a first-generation EGFR inhibitor. And the dynamic changes of the allele frequency of EGFR and TP53 mutants were consistent with total cfDNA levels of the patients. Interestingly, an osimertinib resistance EGFR mutant C797S emerged at Day 355 post-treatment and followed by disease progression in 4 months. In addition to EGFR gene mutations, we further found increasing EGFR copy number associated with drug resistance and cancer progression of this patient. Our study demonstrated that it is feasible using cfDNA for patient follow-up to understand cancer resistance or disease progression through characterization of cancer mutations. Citation Format: Zhigang Kang, Liang Cao. A study of sequencing circulating cell free DNA from lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 533.